A brief insight on ACE receptors role in COVID-19

A brief insight on ACE receptors role in COVID-19

With the novel coronavirus, COVID-19 is spreading across the world and the fact that no drug or treatment has been found against it is creating fear among people. Coronavirus is a large family of enveloped, single-stranded RNA that infects mainly mammals including humans. In humans, coronavirus causes mild to severe respiratory illness. These viruses exhibit strong virulence and are highly contagious. While a person infected, produces mild symptoms, certain individuals respond severely, sometimes leading to death. 

The SARS pandemic, back in 2002 is known to belong to the same family of viruses as COVID-19. According to WHO, SARS rapidly spread through 29 countries, with 8096 confirmed cases, but the current pandemic has surpassed all numbers by infecting over millions of people across the world. Today, it is due to SARS that has resulted in a coordinated effort to develop treatments targeting the virus or host cell components responsible for viral replication.

The deadly virus, COVID-19 enters the human body and binds to the target cells through angiotensin-converting enzyme 2 (ACE2) which is mainly expressed in endothelial cells and Leydig cells. ACE-2, a transmembrane metallo carboxypeptidase, is an enzyme which for years has been important for the treatment of hypertension. With further Polymerase Chain Reaction (PCR) analysis it was determined that the ACE-2 receptor is also present in the lung and gastrointestinal tract, tissues harboring COVID-19. 

Inhibiting ACE2 receptor blocks COVID-19 entry:

ACE-2 belonging to the family of ACE receptors, plays a key role in the Renin-Angiotensin System (RAS) and in the treatment of hypertension. ACE2 is known to degrade angiotensin II and thereby, negatively regulating RAS. Recently experts have revealed that the COVID-19 virus uses ACE-2 receptors as their entry in HeLa cells. Additionally, it was found that by using anti- ACE-2 antibodies in other mammals like monkeys, it was seen that there was an entry blockage of pseudotypes expressing the COVID-19 virus. 

For the virus to enter the host cell, its spike glycoprotein (S) needs to be cleaved at 2 sites, termed S protein primming so the viral and host cells membrane can fuse. A serine protease TMPRSS2 is essential for cleaving the S protein. It was found by treating Calu-3 human lung cell line with a serine inhibitor- camostat mesylate the entry of the COVID-19 virus was partially blocked. Angiotensin-converting enzyme (ACE) inhibitors is also found to play a role in preventing the formation of angiotensin II. ACE multifaceted functions include treating heart failure, controlling high blood pressure, and preventing kidney failure in diabetic patients. 

Existing concerns about ACE inhibitors:

Though ACE inhibitors might seem like a promising solution for COVID-19, there are certain concerns regarding the increased susceptibility to COVID-19. These are considered based on the fact that ACE inhibitors are also used in treating millions of people with hypertension, heart, and kidney disease. When administered with inhibitors, diabetes and hypertension patients were observed to have an increase in ACE2, which in turn would facilitate infection with COVID-19. It is hence hypothesized that treating diabetic and hypertension patients with ACE inhibitors might make them more susceptible to COVID-19. 

Furthermore, several studies have reported that long term usage of ACE inhibitors can modify the adaptive immune response, which is a key and much-needed defense against any infection. These particular effects must be taken into noticed and investigated further in context to COVID-19. 

Road to COVID-19 therapies:

These findings could greatly impact the efforts being taken in developing treatments for the current pandemic. For instance, TMPRSS2 inhibitors can be potentially used to prevent virus entry into the host cells. Though there are certain drawbacks in using ACE inhibitors, there is a lack of scientific evidence and clinical data to support the discontinuing of ACE inhibitors in COVID-19 patients with existing hypertension and diabetes. The proof that reduction in mortality due to ACE inhibitors and the beneficial effects outweigh the theoretical risks. 

Our interpretation of this hypothesis should not lead to changing drugs for patients with diabetes or hypertension, without consulting an expert physician. Though it’s of utmost urgency for the scientific community to come up with some solution for this deadly virus, further research and clinical trials need to be performed before any of the said theory can become a reality. 

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Mutant Polio Virus from Vaccine more infectious than the wild type

Mutant Poliovirus from vaccine more infectious than the wild type

How it all began?

Back in the 20th century, there were many more diseases that worried parents then Polio did. Polio struck during summer, making its way through towns, every few years. Most people were reported to recover quickly, though some suffered temporary or permanent damage leading to paralyzation and even worse, death. With many polio survivors disabled for life, it was a constant reminder to the society the toll it took on young lives. Polio reached the level of epidemic proportions back in the 1900s affecting the infant and young kids, where the infant’s immune system is still aided by maternal antibodies could not fight the virus. 

Polio is caused by a family of viruses belonging to the Enterovirus genus. These viruses are highly contagious usually spreading through contact with people either by oral or nasal secretions, or by contacting a contaminated area. The virus enters the mouth and is found to multiply by the time it reaches the digestive tract, where it continues to multiply. In cases of paralytic polio, the virus makes its way from the digestive tract to the bloodstream attacking nerve cells. 

Development of vaccines to eradicate polio: 

A vaccine is made from a very small amount of wither weak or dead germs that cause the disease, for example-poliovirus. When administered, the vaccine introduces the said virus into the body to trigger an immune response, causing it to recognize and combat the actual disease if encountered in the future. 

 The antibodies specific to the poliovirus was first discovered in 1910. Using immunologic techniques, it was in 1931 different serotypes of the poliovirus were identified. By identifying that the virus can be grown in large amounts using tissue culture, it was just a short time before the first inactivated polio vaccine (IPV) was developed. With human trials being deemed a success, the number of polio cases drastically dropped over the years. Later an improved version of the vaccine using live attenuated virus was developed, which could be administered orally, known as oral poliovirus vaccine (OPV). Soon it became the predominant go-to vaccine for developing countries all over the world, declining the number of cases drastically till a new problem raised recently. 

Vaccine-derived poliovirus:

Over the past few years, more than 10 billion doses of OPV have been administered to millions of children worldwide, preventing more than 10 million cases during that period, bringing down the number of cases drastically. 

So far in the year 2017, only as many as 6 “wild” polio cases were detected worldwide. By wild it means that the number of cases affected by polio “wild type” strain found naturally in the environment. Recently, new cases have been reported of children paralyzed by a vaccine-derived poliovirus. Around nine new cases were identified in countries- Nigeria, the Democratic Republic of the Congo, Central African Republic, and Angola last November, along with Afghanistan and Pakistan. The WHO reported that as long as a single child is infected, all the other children are at risk. 

In developing countries, the oral vaccine is used profusely among all children due to its low cost and accessibility. The vaccine-associated paralytic polio is caused by a strain of poliovirus which was previously termed wild type. The onset was found to be caused by a type 2 virus contained in the oral vaccine. Type 2 virus was a wild type virus eradicated years ago, but in rare cases can mutate into a form that can breach the vaccine protection. 

Erradication possible:

With the COVID-19 outbreak, the WHO has also additionally undertaken the goal of eradicating the new mutant poliovirus before its too late. The role model here is smallpox, which was completely wiped out thanks to a consistent vaccination strategy. The same applies to polio. Similar to smallpox, the polio vaccine also offers impeccable protection, though not applicable to virus mutants. Reports state that the latest mutant outbreak is due to the low vaccination rates. The rise in vaccine-derived polio cases is due to the mutant form of the disease affecting the non-vaccinated children through contaminated matter. 

The coverage of vaccination and hygiene measures must be extended so that the new mutant can no longer continue to survive, the same way the previous polio epidemic in Congo was eradicated. Though the current vaccines appear to be good enough to be effective, the new pathogen is nonetheless a warning. The need for new protectant vaccines is more important now than ever. It is only this way there is a chance of permanently wiping out polio. 

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COVID-19: What you need to be careful of?

COVID-19: What you need to be careful of?

More than 780000 cases of COVID-19 have been reported across the globe. The new coronavirus outbreak has the attention of the entire world as there are no effective medicines or vaccines yet. The virus originated in the Wuhan city of China and spread to numerous countries in almost no time. This does raise multiple questions like what exactly the virus is. Why its transmission rate is so high? And how an individual can avoid catching it? Well, amid this outbreak we will help you know about the virus in detail. Read ahead to gain a brief insight into the challenges the whole world is suffering from and how we all can overcome it.

Understanding the Coronavirus

Coronaviruses are a group of viruses whose exterior layers reflect a crown-like structure. Corona is a Latin word which means crown. There are various types of viruses in this group but most of them cause very slight illness and cold-like symptoms. The pathogenicity of novel Coronavirus has led researchers and scientists across the world to study more about it as there is very little information in the scientific community. Wuhan city of China is considered to be the epicenter of the disease initially from where it spread to numerous countries in no time. The origin of the virus is still not known but some studies suggest that it has been transmitted to humans from the animals.

Symptoms of COVID-19

The symptoms of the COVID-19 are often confusing as they are somewhat similar to the symptoms of common flu. However, the characteristics difference between them is the presence of high fever, sore throat, dry cough, difficulty in breathing and pneumonia in severe conditions. The incubation time for the development of symptoms is considered to be 14 days due to which people suspected of COVID-19 are suggested to quarantine themselves for this period.

Since very little information is available about the virus, researchers and doctors across the globe are contributing crucial information from the recent cases. It is observed that the virus mainly infects people with low immunity. This is the reason that countries with coronavirus outbreak have high infection and death rate among the elderly population. However, it doesn’t stipulate that young people and children are not prone to it. Having weak immunity irrespective of age can make you prone to infections. Therefore, doctors are prescribing for regular exercise and healthy food as a primary effort to protect yourself from the infection.

The major concern over here with the condition is that at the beginning people might not be able to assess the situation (as the grave) due to the mild symptoms associated. In some cases, people confuse the symptoms with that of normal flu and avoid going to the doctor until it becomes severe. During this period, the patient must have come in contact with say ‘n’ number of people which will further infect other ‘n+y’ number of people. This chain continues as the severe symptoms take 14 days to be physically visible. A point comes where there is a sudden outburst of diseases leading to chaos and panic which is often observed in present cases of countries like China, Italy, Iran, the USA, etc.

Precautions to avoid infections

The transmission of coronavirus from an infected person into the atmosphere takes place through the tiny droplets of a sneeze. These droplets though don’t stay suspended in the air for long, it descends and settles onto the surfaces. It is therefore very crucial for every individual to maintain at least 1m of distance from the infected person. Also, one must avoid touching such infected surfaces and later touching their eyes, nose or face. It is therefore very important to wash your hands thoroughly at regular intervals.
To prevent the transmission of the coronavirus, the doctors also suggest avoiding any kind of physical contact with other people such as avoiding handshakes. In case if you are infected with the disease or even with the normal flu, you must sneeze in your elbows rather than in your palms. You can also use handkerchief or tissue to cover your mouth during the sneeze as these practices reduce the chances of the spread of infectious droplets in the atmosphere.

Way ahead

COVID-19 is a disease that may look normal to you due to its mild symptoms at the initial stage. However, the experience in other countries shows that its completely the opposite and one must take effective care as soon as there are visible symptoms. One of the best ways to prevent the spread is to self isolate yourself and undertake prescribed medications. Researchers and scientists across the globe are working hard to come up with potential vaccines and medicine for the disease. But till then we need to consider the basic precautionary steps to avoid escalation of the situation. So, stay safe and spread awareness among your family to help the world fight this disease together. Let’s not forget we all are together in it and we will come out of it together.

Nobel Prize 2019: How Cells Sense and Adapt To Oxygen Availability

Nobel Prize 2019: How Cells Sense and Adapt To Oxygen Availability

The 2019 Nobel Prize in physiology and medicine is awarded to the trio of scientists – William G. Kaeling, Gregg L. Semenza and Sir Peter J. Ratcliffe for the discovery of sensing and adaptation mechanism of cells to oxygen availability.

We all know how crucial oxygen is for the existence of an organism. It helps to convert the food into a useful energy source, which in turn drives multiple biochemical pathways within the biological system. Though we are acquainted with the importance of oxygen for decades, the basic understanding of how cells acclimatize to the shift in the oxygen levels within an organism is yet to be inferred.

The discovery by the trio of scientists has helped in identifying the underlying molecular machineries playing role in modulating the gene expression in response to changing oxygen levels. The findings have also unveiled how fluctuating oxygen levels alter cellular metabolism and physiological function. It will be very useful in developing new strategies to combat various diseases like cancer, anemia and more.

Oxygen – The Key Player

The conversion of food into the energy source in mitochondria is an oxygen-dependent mechanism. This shows a sufficient level of oxygen is very critical. The evolutionary development has helped in coming up with a unique mechanism that helps in maintaining the sufficient levels of oxygen supply to all cells and tissues. For example – the presence of the Carotid body in the neck region is a remarkable illustration of cellular mechanisms adapting to changing levels of oxygen. These bodies consist of specialized cells which mediate the oxygen levels in hypoxia-like condition. Similar to this another significant mechanism is EPO dependent response to hypoxia conditions. Wherein low levels of oxygen lead to an increase in levels of erythropoietin causing a rise in red blood cell production (A process called erythropoiesis). However, the understanding of how this process is dependent on oxygen was missing. To find that scientists started to study the EPO gene. Some of the results showed that certain genetic elements present next to the EPO gene play a vital role in controlling the levels of oxygen.

Meanwhile, Sir Peter Ratcliffe was also studying the same phenomenon. Later both the research group found that the oxygen sensing mechanism is commonly present in almost all cells and tissues. On the other side, scientist Semenza was trying to unfold the cellular components involved behind this sensing mechanism. He found a protein complex named as Hypoxia Inducible Factor (HIF) which binds to DNA segments in oxygen-dependent manner. Scientists soon purified the respective protein and identified associated transcription factors (HIF-1α and ARNT) mediating the sensing mechanism using HIF.

Demystifying the Role of VHL

The level of HIF-1α is inversely proportional to the oxygen levels. Certain studies showed that under normal circumstance HIF-1α is protected from degradation. However, under hypoxia conditions, the HIF-1α undergoes ubiquitin-dependent degradation in the proteasome. But how ubiquitin binds to HIF-1α in an oxygen-dependent manner was a big mystery. The answer to this name from the finding of scientist William Kaelin when he was studying an inherited genetic disease named Hippel-Lindau’s disease (VHL disease). Families with VHL mutations are considered to have a higher risk of cancers. Further studies showed that cells with VHL mutations exhibited increased expression of hypoxia-regulated genes. However, upon reintroduction of the VHL gene into the cells the condition turns back to the normal. This highlighted a significant relation between VHL and hypoxia. Other similar studies showed that VHL is a crucial part of the protein complex playing role in marking cellular components for degradation in proteasome in a ubiquitin-dependent manner. Thus, a key discovery was made which demonstrated the VHL interaction with HIF-1α and its subsequent degradation in an oxygen-dependent manner.

Oxygen regulating VHL & HIF-1α interaction

Another missing piece in the puzzle of understanding the oxygen sensing mechanism by cells was to understand how changing oxygen levels mediate the interaction between VHL & HIF-1α. Upon further investigation, scientists discovered hydroxylation as a key in the entire process. They discovered that under normal levels of oxygen, two hydroxyl groups are added to HIF-1α at certain sites, a process known as prolyl hydroxylation. This allows VHL to recognize HIF-1α leading to subsequent binding and controlling degradation of HIF-1α in an oxygen-dependent manner. Scientists soon identified the enzymes involved in the hydroxylation process. Later, certain findings also showed that genes involved in the activation of HIF-1α are also regulated by oxygen-dependent hydroxylation.

Unveiling the oxygen sensing mechanism in the organism is breakthrough research due to its wide application. From the adaptive response in muscle during exercise to immune system response in the body, oxygen sensing plays a very critical role in channelizing these biological processes.  Besides this, it also has a significant role to play in a number of diseases such as anaemia, cancer and more. The Noble prize-winning research has led the path for many other scientists and pharmaceutical companies to develop new drugs targeting this oxygen-sensing mechanism.

Antibodies Targeting Influenza Viruses – A Hope for Universal Vaccine

Antibodies Targeting Influenza Viruses – A Hope for Universal Vaccine

For most of us, influenza infection resolves on its own but in many cases, it can have severe outcomes if ignored. Therefore, scientists across the globe are looking for some effective method to prevent influenza infection. Many pieces of research have been carried out where the scientists are developing antibodies to efficiently target the influenza virus.

The major reason for failure in developing an effective treatment method against the influenza virus is its constantly changing nature, wherein new strains develop regularly. So if you had influenza in the past with say strain-A, your body will have antibodies against it. But next time when you are infected again with some other strain of influenza your body will recognize it as new. This is the reason that no universal vaccine is available till now. However, recent research work by Daniel Stadlbauer et.al embarks a new ray of hope for the development of a universal vaccine against the influenza virus.

Antibody Targeting Neuraminidase

There are multiple influenza virus strains that require designing a new vaccine almost every year. This is the reason vaccine shots against flu are needed to be taken every year, unlike any other infection. But imagine what if we have an antibody that can target all these strains? Such an antibody can be used to design a universal vaccine that can target all strains of influenza including, swine and other avian influenza viruses.

There are certain protein molecules on the surface of the virus which help it to enter the host cells or to replicate in the host body. One such protein is ‘Neuraminidase’ which is the center of the present study. The researchers found a unique antibody that targets the conserved region of this protein, eventually blocking the viral replication and preventing the further spread of infection.

Till now, Tamiflu a well-known drug is used for flu treatment which works by targeting neuraminidase. But as discussed earlier, the virus exists in multiple strains due to variability in neuraminidase protein; in such cases, the existing drugs are not that effective. Moreover, the increasing burden of drug resistance is also a cause of concern. The recent finding of a unique antibody capable of targeting multiple influenza strains can help in overcoming the drawbacks of existing treatment methods.

The researchers tested blood samples from flue patients and observed unique behavior. They found that apart from the common activity of antibody against hemagglutinin, there were some other antibodies targeting something else. Upon investigating three of these unknown antibodies, the researchers found that the antibodies were blocking the neuraminidase activity in all types of known flu viruses. Scientists were amazed by results as for the first time some antibodies have shown activity against a wide range of virus subtypes. Otherwise earlier the activity was limited only to the certain subtype of influenza. But in the present study, the antibodies were able to cross between influenza A and influenza B, showing an extensive range of activity.

Antibody – 1GO1 and mice studies

To analyze the effectiveness of antibodies against the severe cases of flu, researchers tested the antibodies in mice. These mice were given a lethal dose of influenza virus before the introduction of antibodies. The results obtained were astonishing as all three antibodies showed positive results with one antibody named-1GO1 capable of protecting against more than 11 strains of influenza (both human and non-human strains)

It is suggested that for effective use of Tamiflu, it should be administered within 24 hours of infection. However, with the help of present antibodies identified, the administration even after 72 hours of infections showed positive results, which is quite remarkable.  Thus, a similar drug based on these antibodies can be designed to treat influenza infection but to do so scientist need to further understand how these antibodies actually interfere in neuraminidase activity.

Structural and functional analyses

To understand the underlying mechanism behind the antibody-based blocking of viral replication, scientists carried out the structural and functional analyses. They mapped the structures of the antibodies bound to neuraminidase. The findings showed that each of the antibodies had a loop-like structure that slides into the active site of neuraminidase just like a stick between the gears. This interferes with the normal functioning of neuraminidase thereby blocking the release of new virus particles from the infected host cells. This further breaks the entire replication cycle important for the spread of infection.

The most noticing part of the findings was the insertion of a loop by antibodies within the conserved active site without contacting the hypervariable regions in the surrounding. This allowed targeting a broad range of neuraminidase in different influenza viruses than any of the earlier methods.

The study reveals that using these antibodies can provide protection from a wide range of influenza virus strains as it targets the conserved regions of the neuraminidase active site. These conserved regions remain almost the same even across the distantly related virus strains. Thus, using these antibodies can help in universal vaccine development against influenza.

Till now, neuraminidase as a target for the vaccine has been ignored for long but the present study highlights its importance. To take this ahead, researchers are working on developing new and improved treatments and vaccines for influenza based on antibody 1G01.

Scientists Help Immune System Find Hidden Cancer Cells

Scientists Help Immune System Find Hidden Cancer Cells

Cancer is a widely studied topic in bioscience research but yet remains to be mostly unknown and difficult to treat. However, the recent developments in cancer research over the past decade have helped the scientific community to come up with effective treatment methods. But still, one of the most common problems faced in treating cancer cells is difficulty in locating them for efficient targeting. Recently, scientists from Yale University have developed a new system that can help our immune system find the hidden cancer cells and kill them. The research has been published in Journal Nature Immunology.

Why this study holds importance?

It is a known fact that there exists a number of immunotherapies for treating cancers. But these therapies have certain shortcomings as they either don’t work on all patients or are inefficient in different cancer types. The major reason behind this is the failure of these therapies in identifying the cancer cells which reduces their effectiveness. This highlights an urgent need for a more targeted approach that can help curb the menace of cancer.

The development of a new system by scientists in the present study is considered to overcome the drawbacks of the earlier immune therapies. Researchers report that upon testing the new system in mice it has shown positive response against the melanoma, triple-negative breast, and pancreatic tumors, even for those tumors which are situated at a distant location from the primary tumor.

“This is an entirely new form of immunotherapy,” said Sidi Chen, senior author.

How the new system – MAEGI works?

The researchers developed a new system to target the cancer cells which combines the viral gene therapy and CRISPR based gene-editing technology. Unlike the traditional method of searching and making edits at the DNA level by incorporation of new genes, the present system uses a much more targeted approach.

The new system named as MAEGI stands for Multiplexed Activation of Endogenous Gene as Immunotherapy. This system works by searching numerous cancer-causing genes, marking their location by mimicking GPS and subsequently intensifying the signal of these locations for precise targeting.

For instance, you can consider that the new system dresses up the tumor cells in a unique manner that can be easily identified by the immune system of our body and eventually eliminate them. For this, the cold tumors cells lacking any immune cells are converted into hot tumors cells which are packed with tons of immune cells.

“And once those cells are identified, the immune system immediately recognizes them if they show up in the future,” Chen said. The new system, in theory, should be effective against many cancer types, including those currently resistant to immunotherapy, he said.

The researchers will be further optimizing this system to make the manufacturing process easier. Once optimization is done it will be subjected to clinical trials in potential cancer patients.

No wonder that cancer is a rising menace in the present world. Though many therapies are available we still need highly effective methods to treat cancer. The development of the immunotherapy-based system has given rise to a ray of hope for a more effective and proficient treatment that not only treats primary tumor cells but also the distant ones. Let’s look forward to this new development and hope for the best outcomes in subsequent clinical trials.

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